Current topics in the surgical treatments for hepatocellular carcinoma

Abstract Treatment strategy for hepatocellular carcinoma (HCC) requires optimal selection of therapies based on various factors related to tumor condition and liver functional reserve. Although several evidence‐based guidelines have been proposed for the treatment of HCC, the criteria and range of indications differ among these guidelines according to the circumstances of each country. In European nations and the USA, patients with the Barcelona Clinic Liver Cancer stage 0‐A are subjects for surgical resection, whereas in Asian countries, even those with the intermediate stage are regarded as surgical candidates. Furthermore, since the recent introduction and rapidly widely spreading use of laparoscopic liver resection, this technique has become an important treatment option for surgical resection. In this review article, we overview the current topics of treatment of HCC with a special focus on surgical therapy.


| INTRODUCTION
Approximately 850 000 people die of hepatocellular carcinoma (HCC) per year, worldwide 1,2 and it is the second most common cause of cancer death. Approximately half of all primary liver cancers occur in China (395 000 people per year), whereas Northern Europe has the lowest incidence of the tumor. 3 The incidence of hepatocellular carcinoma has increased in many countries, depending on hepatitis B and C virus infection and alcohol-related liver disease. Other risk factors include smoking, obesity, nonalcoholic fatty liver disease (NAFLD) and diabetes. 4 Resection is the mainstay of treatment for resectable HCC. 5 We review the current topics of HCC treatment regarding the position of surgical treatments from the standpoints of comparison of guidelines, early-stage HCC and advanced-stage HCC. We also discus laparoscopic liver resection, a surgical technique that has become popular recently.

| CURREN T STATUS OF TH E TREATMENT
GUID ELINES FOR HEPATOCELLULAR CARCINOMA 2.1 | TNM staging The TNM staging system is based on three key pieces of information. T describes the number and size of the primary tumor(s), and whether the tumor has grown into nearby blood vessels. N describes the extent of spread to regional lymph nodes. M indicates whether the tumor has metastasized to distant parts of the body. The most recent version of the TMN staging system (8th edition) was published in 2017, coming into effect on 1 January 2018. 7 Some significant changes in the T classification have been made, relative to the 7th edition. T1 was subdivided into two subcategories: T1a (solitary tumor ≤2 cm) and T1b (solitary tumor >2 cm, without vascular invasion). There was no change to the T2 category (solitary tumor with vascular invasion or multiple tumors, none >5 cm). The previous T3a category was re-categorized as T3 (multiple tumors, at least one of which is >5 cm), whereas tumors that were previously categorized as T3b are now included in T4 (tumors involving a major branch of the portal vein or hepatic vein, or tumors with direct invasion of adjacent organs or perforation of the visceral peritoneum).
Because the TNM staging system lacks factors related to liver functional reserve, it may not be adequate for patients with severe underlying liver disease. 9

| BCLC staging classification
The BCLC group was created in 1986 by Jordi Bruix and Concepcio Bru. Since the staging system was first published in 1999, it has been updated according to evidence-based data. 8 The  (Table 1). 13 In general, indication for hepatic resection is decided based on liver function and extent of tumor development. Appropriate candidates for surgical treatment vary according to the guidelines.

| Liver function
Liver function is assessed on the basis of the Child-Pugh classification, the presence of portal hypertension, such as thrombocytopenia associated with varicose veins and splenomegaly, and the presence of elevated serum bilirubin concentrations. According to the BCLC staging, criteria for surgical candidates include those classified as Child-Pugh class A, absence of portal hypertension, and elevated bilirubin. 10  According to the National Comprehensive Cancer Network (NCCN), Japanese, and Korean guidelines, it is recommended not to consider mild portal hypertension as a contraindication to surgical treatments. It is evident that clinically significant portal hypertension increases the risk of postoperative mortality and clinical decompensation. 16 However, further investigation is required to determine the severity of portal hypertension, which may not impair the safety of surgery. It has been reported that portal hypertension may not affect the prognosis after radiofrequency ablation (RFA). 17 In the Japanese and Korean guidelines, liver functional reserve is assessed by the indocyanine green (ICG) test, in addition to the Child-Pugh classification system. 18 5,15,20,21 The EASL-EORTC guidelines added a recommendation of anatomical resection that has ensured a surgical approach, based on sound oncological principles, although associated with a modest decrease in early recurrence. 22,23 The guidelines also refer to the choice of preoperative portal vein embolization (PVE) in order to increase the residual liver volume if a major resection is planned. 5 The AASLD guidelines were based on the BCLC staging system in the previous version (2011). 14  The Japanese guidelines also recommend that resection can be considered in patients with ≤3 nodules, regardless of tumor size.
In addition, portal vein tumor thrombus should not be precluded from surgical resection, so that these guidelines recommend the widest surgical indication. 18  showed the superiority of resection (Table 2). However, the conclusion stating the superiority of resection to RFA cannot be accepted completely because some studies included patients with HCC of 2 cm or greater in size, for which ablation seems ineffective, and because RFA was more likely to be selected for patients with impaired liver functional reserve, so that there may be a difference in patient background, suggesting the possibility of selection bias. 39,48 Indeed, in daily clinical practice, treatment regimens are determined not only by the size and number of tumors but also by the location of tumors and their relationship to blood vessels, as well as the liver functional reserve of patients with Child A classification. Some reports also discussed the cost-benefit of treatments, in addition to tumor factors and liver functional reserve, and suggested that the optimal treatment should be considered not only based on tumor factors defined in the guidelines but also on more detailed conditions. 49  It has been shown that preoperative radiotherapy for HCC associated with PVTT reduced the size of PVTT and showed better progression-free and survival rates than surgery alone, 61 suggesting efficacy of preoperative radiotherapy for PVTT. From an oncological point of view, laparoscopic liver resection has been shown to be non-inferior to laparotomy in many retrospective studies, including those which used PSM to minimize differences in the backgrounds of patients. As shown in Table 3 84 The differences are considered to be caused by low surgical stress, including less blood loss and less tissue manipulation, and so on. The feature of laparoscopic approach will lead to expanding the surgical indications for HCC with a background of chronic liver disease.
Safety is the primary concern regarding the introduction of laparoscopic liver resection; therefore, guidelines are needed for that purpose. In addition to conventional classification (minor and major liver resection), a scoring system of surgical difficulty on the basis of liver functional reserve and tumor factors, including tumor location and relationship to major vessels, has been proposed in an attempt to serve as a guideline for training, [85][86][87] and has been validated to correlate with surgical outcome in the clinical setting. 88-90 A step-by-step training system appropriate for the difficulty score and individual surgical skill can lead to safe expansion of the indication of LLR.

| CONCLUSION S
We have reviewed the current topics of HCC treatment, focusing on surgical therapy. Introduction of a new modality for ablation and a